1. Field of the Invention
The present invention relates to quantitative spectroscopy in turbid media or highly scattering media and more particularly to absolute measurements of various blood constituents in living tissue by non-invasive, non-harmful methods.
2. Description of Related Art
Near infrared radiation with wavelengths of 600-1400 nanometers passes easily through living tissue. However, these same wavelengths are variously affected by tissue oxyhemoglobin concentration, e.g., on the basis of hemoglobin absorbance. The overall range is limited in wavelength, e.g., on the long wavelength side of the spectrum, longer than 1400 nanometers, by water absorption, and on the short wavelength side of the spectrum, shorter than 600 nanometers, by blood absorption. Between these higher and lower limits, the light that does penetrate the tissue is highly diffuse due to scattering. Such diffusion can otherwise obscure information that could be extracted from the non-scattered light. See E. M. Sevick et al., "Quantitation of Time- and Frequency-Resolved Optical Spectra for the Determination of Tissue Oxygenation," Analytical Biochemistry 195, pp. 330-351 (1991).
Optical diagnostic systems have been built to take advantage of the near infrared translucence of living tissue, but these prior art systems are seriously handicapped by the photon scatter that occurs within the highly diffuse tissue. One of the earliest used optical techniques, called pulse oximetry, was only able to provide estimates of the oxygen saturation of blood, e.g., by using the phenomenon of differential transmission of light caused by oxyhemoglobin and reduced hemoglobin. Saturated oxygen (SaO.sub.2) is defined as the percentage of oxygen bound to hemoglobin compared to the total hemoglobin available for reversible oxygen binding. Unfortunately, with pulse oximetry the absolute concentration of free oxygen in the blood could not be discerned, because it has no NIR signatuare. Only the ratio of oxyhemoglobin to total hemoglobin can be determined through human tissue.
Quantitative spectroscopy through tissue with optical radiation is facilitated by the use of scatter elimination techniques, which fix the photon path length. Measurements of the attenuation due to the material of interest in the medium is difficult without a means to discriminate the non-scattered-photons from the scattered-photons, because the amount of medium involved (i.e. pathlength) is indeterminate. In useful applications, the exact path lengths must be determined for sub-surface light penetrations of tissue that range up to several millimeters.
Time-domain and frequency-domain methods can be used for the discrimination of light that has undergone considerable scattering to selectively detect the non-scattered, first arriving photons. Scattered photons necessarily travel over longer distances and take more uncertain pathways than do ballistic or quasi-coherent photons. The non-scattered photons traverse much shorter path lengths and exit the medium in a small, forward cone. The best quantitative information is carried in the photons that are relatively non-scattered, and these arrive first at the detector from the medium. Time-resolved techniques have conventionally been used to discriminate between scattered and non-scattered light exiting tissues based on time-of-flight. Optical coherence techniques rely on the short coherence length of a broadband low-coherence light source to provide time-of-flight information interferometrically via autocorrelations. Measurements are therefore restricted to relatively non-scattered, first arriving (i.e. ballistic) photons.
Time domain techniques, such as streak cameras, require sub-picosecond laser systems which are expensive, non-compact, and complicated. Frequency-domain techniques, however, use inexpensive optical sources, optical low-coherence reflectometry (OLCR), and avoid the need for complicated systems. State-of-the-art reflectometers use diode light sources and fiberoptics that make for compact and modular systems that are capable of micrometer spatial resolutions and high detection sensitivities.
The relative transparency of biological tissues to near infrared (NIR) light allows the absorption properties of intact organs to be monitored non-invasively. The NIR absorption caused by hemoglobin and cytochrome oxidase can be measured and used to monitor changes in blood and tissue oxygenation. Such measurement methods were first applied to the brain of cats and subsequently to the brains of newborn infants and adults. Recently, methods for the absolute quantitation of cerebral blood flow and blood volume have been developed and applied to newborn infants and adults. The possibility of imaging of tissue oxygenation by NIR light has also been studied by various groups.
Quantitative interpretation of spectroscopic data using the Beer-Lambert law requires that the optical pathlength be known, otherwise the light intensity measurement is meaningless because the distance over which it was attenuated is unknown. At best, the prior art only approximates the pathlength. In near infrared spectroscopy (NIRS), light scattering by the tissues prevents detecting all the light that entered the tissues. The source light travels along a distribution of paths. It has, however, previously been shown that a modified Beer-Lambert law can be applied to quantify changes in chromophore concentration from the measured changes in tissue attenuation. This modified law uses the differential pathlength, which is defined as the local gradient of the attenuation versus the absorption coefficient .mu..sub.a of tissue. It has been shown experimentally that the differential pathlength can be approximated by measuring the mean distance L traveled across the tissue by picosecond light pulses or by measuring the phase shift of a frequency modulated light source. The differential pathlength factor which is obtained when the mean pathlength &lt;L&gt; is divided by the distance between light source and detector optrodes, has been shown to be approximately constant once the optrode spacing exceeds 2.5 cm.
To date, the use of differential pathlength factors have only been demonstrated to be valid for homogeneous mediums. But real organs consist of various tissue components that have different optical parameters. Therefore, for accurate quantitation of data, it is important to understand the nature of light transport through an inhomogeneous medium and to know the effective optical pathlengths within the various portions of the medium.
M. Hiraoka discusses various methods for calculating light transport through tissue, in "A Monte Carlo investigation of optical pathlength in inhomogeneous tissue and its application to near-infrared spectroscopy", Phys. Med. Biol. 38, pp. 1859-1876 (1993). One approach is to seek an analytical solution of the diffusion equation. However, this has only succeeded under restricted geometries and for a homogeneous medium. A second approach is the "Monte Carlo" method which can be applied to inhomogeneous media and has the advantage of being able to calculate the pathlength directly. This method keeps track of individual photon histories but requires considerable computation time. A third approach is to solve the diffusion equation numerically by the finite-difference method. This has been successful under restricted conditions for all inhomogeneous media. A fourth approach is to solve the diffusion equation by the finite-element method, which can be applied to the complex geometries of an inhomogeneous medium and has the advantage of fast calculation time. However, it does not calculate individual photon histories.
The lack of accurate pathlength information has therefore complicated an otherwise useful measurement tool.